HOX gene mutation/rocker bottom foot

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Research from Am J Hum Genet. May 2004 14;75(1).

A HOX Gene Mutation in a Family with Isolated Congenital Vertical Talus

and Charcot-Marie-Tooth Disease.

Shrimpton AE, Levinsohn EM, Yozawitz JM, Packard DS Jr, Cady RB,

Middleton FA, Persico AM, Hootnick DR.

Department of Clinical Pathology, State University of New York,

Syracuse, NY, 13210, USA.

Congenital vertical talus (CVT), also known as " rocker-bottom foot "

deformity, is a dislocation of the talonavicular joint, with rigid

dorsal dislocation of the navicular over the neck of the talus. This

condition is usually associated with multiple other congenital

deformities and only rarely is an isolated deformity. The reported

familial cases are consistent with an autosomal dominant mode of

inheritance with incomplete penetrance. In contrast, Charcot-Marie-Tooth

disease (CMT) is thought to be a completely distinct heterogeneous group

of disorders, with foot abnormalities that typically develop a

high-arched " claw foot " appearance later in life.

In the present study, DNA was isolated from 36 members of a single

upstate (northern) New York white family of Italian descent in which

both CVT and CMT were segregating. Whole-genome linkage analysis with

Affymetrix GeneChip Mapping 10K Array defined a 7-Mb critical region on

chromosome 2q31, which led to candidate-gene sequencing of six HOX genes

and detection of a single missense mutation, M319K (956T-->A), in the

HOXD10 gene. In the study family, this mutation was fully penetrant and

exhibited significant evidence of linkage (LOD 6.33; theta =0), and it

very likely accounts for both CVT and CMT in heterozygotes.